Derivatives of naphthalene with COMT inhibiting activity

ABSTRACT

Compounds of formula (I′), wherein A, R 1  to R 3  and t are as defined in the disclosure, exhibit COMT enzyme inhibiting activity so that they are useful as COMT inhibitors.

This application is a national stage filing of PCT InternationalApplication No. PCT/FI01/00797, filed on Sep. 14, 2001. This applicationalso claims the benefit of priority under 35 U.S.C. §119(a) to Finnishpatent application no. 20002044, filed on Sep. 15, 2000.

FIELD OF THE INVENTION

The present invention relates to derivatives of naphthalene andpharmaceutically acceptable salts and esters thereof. The inventionfurther relates to pharmaceutical compositions thereof and to their useas inhibitors of catechol-O-methyltransferase (COMT) enzyme.

BRIEF DESCRIPTION OF THE PRIOR ART

Compounds with COMT inhibiting activity are already known. For example,derivatives of catechols have been disclosed i.a. in U.S. Pat. Nos.5,446,194, 5,389,653 and WO-A-96 37456. U.S. Pat. Nos. 5,650,439 and3,973,608 relate to isoflavones and, respectively, to a purpurogallinderivative with COMT inhibiting activity. Furthermore, R. T. Borchardtand P. Bhatia disclose in J. Med. Chem., vol.25, 1982, p.263-271,analogues of 5,6-dihydroxyindole (5,6-DHI) as COMT inhibitors. COMTinhibitors are used i.a. in the treatment of Parkinson's disease.COMT-inhibitors have also indicated to be useful in the treatment ofi.a. hypertension, heart failure and depression (cf. e.g. U.S. Pat. No.5,446,194 above) as well as inhibitors for the prevention of diabeticvascular dysfunctions (cf. WO-A-98 27973).

SUMMARY OF THE INVENTION

The object of the present invention is to provide further compounds withcatechol-O-methyltransferase enzyme inhibiting activity.

The invention also provides compounds for the treatment of disorders orconditions wherein inhibition of COMT is indicated to be useful, as wellas a use thereof for the manufacture of a medicament to be used as aCOMT inhibiting agent. Furthermore, pharmaceutical compositionscontaining the present compounds are provided.

DETAILED DESCRIPTION OF THE INVENTION

The invention thus provides compounds of the general formula I′:

-   -   wherein the two OH— substituents in the phenyl moiety are in a        position ortho to one another and R1 in a position ortho to one        of the hydroxy groups;    -   and wherein    -   “A” is a fused ring moiety selected from benzo ring and a        6-membered heteroaromatic ring which contains one or two N        heteroatoms;    -   R₁ is NO₂, CN, CHO, CF₃ or (C₁-C₆)alkyl-CO—;    -   t is 0, 1, 2, 3 or 4;    -   each R₂ is selected independently from OH, halogen, NO₂, SH,        NH₂, C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy,        OH—(C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl,        halo-(C₁C₆)alkyl, mono- or di(C₁-C₆)alkylamino, SO₂R₄,        (C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N— optionally        substituted with one to three substituents R₆,        —(Y)_(n)—(B)_(m)—COOH and —(Y)_(n)—(B)_(m)—R₅;    -   R₃ is H, NO₂, CN, CHO, halogen, CF₃ or (C₁-C₆)alkyl; and    -   R₄ is (C₁-C₆)alkyl, NH₂, OH or mono- or di(C₁-C₆)alkylamino;    -   m is 0 or 1;    -   n is 0 or 1;    -   Y is —CO— or —CHOH—;    -   B is (C₁-C₆)alkylene or (C₂-C₆)alkenylene;    -   R₅ is phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- to 10-membered        heterocyclyl with one to four heteroatoms each selected        independently from N, O and S, wherein the said phenyl,        naphthyl, (C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclyl is        optionally substituted with one to five substituents R₆,    -   or R₅ is    -   each R₆ is selected independently from OH, halogen, COOH,        5-tetrazolyl, NO₂, SH, NH₂, CN, CHO, ═O, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino,        CO—(C₁-C₆)alkyl, CO—NH₂, mono- or di(C₁-C₆)alkylamino-CO—, NHOH,        CONHOH or SO₂R₄;    -   or pharmaceutically acceptable salts or esters thereof.

As a subgroup of the compounds I′ the invention provides new compoundsof formula I,

-   -   wherein the two OH— substituents in the phenyl moiety are in a        position ortho to one another and R₁ in a position ortho to one        of the hydroxy groups;    -   and wherein    -   A and R₂ are as defined above;    -   t is 1, 2, 3 or 4;    -   R₁ is NO₂, CN, CHO or CF₃; and    -   R₃ is H, NO₂, CN, CHO, halogen, CF₃ or CH₃;    -   or pharmaceutically acceptable salts or pharmaceutically        acceptable esters thereof.

The compounds of formula I′ and I exhibit COMT inhibiting activity andcan thus be used as therapeuticals for the treatment of diseases orconditions wherein COMT inhibitors are indicated to be useful, e.g. forthe treatment of Parkinson's disease.

The two OH-substitutents in the compounds of formulae I′ and/or I can bein the 1,2-positions, 2,3-positions or 3,4-positions, and preferably inthe 2,3-positions, according to the numbering of the above formula I′.

The following subgroups (1) to (23) of compounds of formula I′ or Itaken alone or in any combination with each other are preferable,

-   -   (1) R₁ is NO₂, CN, CHO or CF₃, e.g. NO₂, CN or CHO, such as NO₂        or CN, e.g. NO₂;    -   (2) t is 1, 2 or 3, e.g. 1 or 2, such as 1; or in the compounds        I′ t is 0, 1 or 2;

(3) R₃ is H, methyl, halogen, NO₂ or CHO, such as H or halogen, e.g. H;

-   -   (4) A is a fused benzene ring;    -   (5) A is a fused 6-membered heteroaromatic ring which contains 1        or 2, e.g. 1, heteroatoms selected from N;    -   (6) each R₂ is selected independently from OH, halogen, NO₂,        NH₂, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy,        OH—(C₁-₆)alkyl, NH₂—(C₁-C₆)alkyl, halo-(C₁-C₆)alkyl, mono- or        di(C₁-C₆)alkylamino, SO₂R₄ (wherein R₄ is (C₁-C₆)alkyl, OH, NH₂        or mono- or di(C₁-C₆)alkylamino, e.g. OH, NH₂ or mono- or        di(C₁-C₆)alkylamino, such as mono- or di(C₁-C₆)alkylamino),        (C₁-C₂₀)alkyl-CO—, e.g. (C₁-C₉)alkyl-CO—, such as        (C₁-C₆)alkyl-CO—halo-(C₁-C₆)alkyl-CO—, phenyl-N═N—        (unsubstituted or substituted with one to three, e.g. one or        two, e.g. one, substituent(s) R₆), —(Y)_(n)—(B)_(m)—COOH (e.g.        —(B)_(m)—COOH and —Y—B—COOH) and —(Y)_(n—(B)) _(m)—R₅; wherein n        is 0 or 1; m is 0 or 1; Y is —CO— or —CHOH—, e.g. —CO—; B is        (C₁-C₆)alkylene or (C₂-C₆)alkenylene, e.g. (C₁-C₆)alkylene; R₅        is phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- to 10-membered,        e.g. 5- or 6-membered, heterocyclyl with one to four heteroatoms        each selected independently from N, O and S, e.g. phenyl,        (C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclic ring with        one to four heteroatoms each selected independently from N, O        and S (e.g. piperidyl, piperazinyl, morpholinyl, tetrazolyl,        pyrrolyl, pyrrolinyl, pyrrolidinyl, thienyl, furyl, oxadiazolyl,        isoindolinyl, pyridazinyl or pyridyl, e.g. tetrazolyl,        piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrrolidinyl,        pyrrolinyl or pyridyl, such as tetrazolyl, piperazinyl, pyrrolyl        or pyrrolinyl, e.g. piperazinyl, pyrrolyl or pyrrolinyl) each of        which is optionally substituted with one to five, e.g. one to        three, such as one or two, e.g. one, substituent(s) R₆ as        defined above or below; or R₅ is    -   (7) each R₂ is selected independently from NO₂, NH₂, OH, SO₂R₄        (wherein R₄ is OH, NH₂ or mono- or di(C₁-C₆)alkylamino, e.g.        mono- or di(C₁-C₆)alkylamino), (C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl,        (C₁-C₉)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N— (wherein        the phenyl moiety is unsubstituted or substituted with one to        three, e.g. one or two, e.g. one, substituent(s) R₆),        —(Y)_(n)—(B)_(m)—COOH (e.g. —(B)_(m)—COOH and —Y—B—COOH) and        —(Y)_(n)—(B)_(m)—R₅; wherein n is 0; or n is 1 and Y is —CO— or        —CHOH—, e.g. —CO—; m is 0; or m is 1 and B is (C₁-C₆)alkylene or        (C₂-C₆)alkenylene, e.g. (C₁-C₆)alkylene; R₅ is phenyl,        naphthyl,(C₃-C₇)cycloalkyl or 5- to 10-membered, e.g. 5- or        6-membered, heterocyclic ring with one to four heteroatoms each        selected independently from N, O and S, e.g. phenyl,        (C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclic ring with        one to four heteroatoms each selected independently from N, O        and S (e.g. piperidyl, piperazinyl, morpholinyl, tetrazolyl,        pyrrolyl, pyrrolinyl, pyrrolidinyl, thienyl, furyl, oxadiazolyl,        isoindolinyl, pyridazinyl or pyridyl, e.g. tetrazolyl,        piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrrolidinyl,        pyrrolinyl or pyridyl, such as tetrazolyl, piperazinyl, pyrrolyl        or pyrrolinyl, e.g. piperazinyl, pyrrolyl or pyrrolinyl) each of        which is unsubstituted or substituted with one to five, e.g. one        to three, such as one or two, substituent(s) R₆ as defined above        or below;    -   (8) R₂ is selected independently from SO₂R₄ (wherein R₄ is OH,        NH₂ or mono- or di(C₁-C₆)alkylamino), phenyl-N═N— (unsubstituted        or substituted with one to three, e.g. one or two, e.g. one,        substituents R₆), —(Y)_(n)—(B)_(m)—COOH and —(Y)_(n)—(B)_(m)—R₅;        wherein n is 0; or n is 1 and Y is —CO— or —CHOH—, e.g. —CO—; m        is 0; or m is 1 and B is (C₁-C₆)alkylene or (C₂-C₆)alkenylene,        e.g. (C₁-C₆)alkylene; and R₅ is as defined above or below; e.g.        R₂ is SO₂R₄ (wherein R₄ is as defined above or below),        phenyl-N═N— (wherein the phenyl moiety is unsubstituted or        substituted with one to three, e.g. one or two, e.g. one,        substituent(s) R₆), —(Y)_(n)—(B)_(m)—COOH and        —(Y)_(n)—(B)_(m)—R₅;    -   (9) R₂ is selected independently from NO₂, NH₂, OH, SO₂R₄        (wherein R₄ is OH, NH₂ or mono- or di(C₁-C₆)alkylamino, e.g.        mono- or di(C₁-C₆)alkylamino), (C₁-C₆)alkyl, (C₁-C₆)alkoxy,        NH₂—(C₁-C₆)alkyl, (C₁-C₉)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—,        phenyl-N═N— (wherein the phenyl moiety is unsubstituted or        substituted with one to three, e.g. one or two, e.g. one,        substituent(s) R₆) and —(Y)_(n)—(B)_(m)—R₅; wherein n is 0; or n        is 1 and Y is —CO— or —CHOH—, e.g. —CO—; m is 0; or m is 1 and B        is (C₁-C₆)alkylene or (C₂-C₆)alkenylene, e.g. (C₁-C₆)alkylene;        e.g. R₂ is selected from (C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl,        (C₁-C₉)alkyl-CO—, halo-(C₁C₆)alkyl-CO—, phenyl-N═N— (wherein the        phenyl moiety is unsubstituted or substituted with one to three,        e.g. one or two, e.g. one, substituent(s) R₆) and        —(Y)_(n)—(B)_(m)—R₅, wherein Y, B n, m and R₅ are as defined        above or below;    -   (10) t is 1 or 2 and R₂ or, resp., one of R₂ is as defined in        point (8) or (9) above;    -   (11) t is 2 or 3, e.g. 2, and one of R₂ is as defined in        point (8) and the other R₂ is/are selected independently from        OH, halogen, NO₂, NH₂, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,        (C₁-C₆)alkoxy, OH—(C₁-C₆)alkyl, halo-(C₁-C₆)alkyl,        NH₂—(C₁-C₆)alkyl, (C₁-C₉)alkyl-CO, halo-(C₁-C₆)alkyl-CO— and        mono- or di(C₁-C₆)alkylamino; e.g. OH, halogen, (C₁-C₆)alkyl and        (C₁-C₆)alkoxy; e.g. OH and (C₁-C₆)alkyl;    -   (12) R₅ is phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- or        6-membered heterocyclic ring with one to four heteroatoms each        selected independently from N, O and S, e.g. phenyl or        (C₃-C₇)cycloalkyl, preferably phenyl, or 5- or 6-membered        heterocyclic ring with one to four heteroatoms each selected        independently from N, O and S (e.g. piperidyl, piperazinyl,        morpholinyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,        thienyl, furyl, oxadiazolyl, pyridazinyl or pyridyl, e.g.        tetrazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, morpholinyl,        piperazinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl or pyridyl, such        as tetrazolyl, piperazinyl, pyrrolyl, pyrrolidinyl or        pyrrolinyl, e.g. piperazinyl, pyrrolyl or pyrrolinyl); each        unsubstituted or substituted with one or two R₆ as defined above        or below;    -   (13) R₅ is e.g. phenyl optionally substituted with one or two,        e.g. one, substituent(s) R₆ as defined above or below; or R₅ is        5-tetrazolyl;    -   (14) R₅ is phenyl, piperidyl, piperazinyl, morpholinyl,        tetrazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, thienyl, furyl,        oxadiazolyl, isoindolinyl, pyridazinyl or pyridyl, e.g. phenyl,        tetrazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, morpholinyl,        piperazinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl or pyridyl, such        as phenyl, tetrazolyl, piperazinyl, pyrrolyl, pyrrolidinyl or        pyrrolinyl, e.g. phenyl, piperazinyl, pyrrolyl each        unsubstituted or substituted with one or two R₆ as defined above        or below; or pyrrolinyl substituted with R₆ as defined above or        below;    -   (15) each R₆ is selected independently from OH, halogen, COOH,        5-tetrazolyl, —NHOH, —CONHOH, —CO—NH₂, NO₂, SH, NH₂, CN, CHO,        ═O, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo-(C₁-C₆)alkyl (e.g. CF₃),        mono- or di(C₁-C₆)alkylamino, —CO—(C₁-C₆)alkyl, mono- or        di(C₁-C₆)alkylamino-CO— and SO₂R₄ (wherein R₄ is OH, NH₂ or        mono- or di(C₁-C₆)alkylamino, e.g. mono- or        di(C₁-C₆)alkylamino); e.g. R₆ is selected from OH, ═O, halogen,        COOH, 5-tetrazolyl, —NHOH, —CONHOH, NO₂, NH₂, CN, CHO,        (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo-(C₁-C₆)alkyl, mono- or        di(C₁-C₆)alkylamino, —CO—(C₁-C₆)alkyl, —CO—NH₂ and mono- or di        (C₁-C₆)alkylamino-CO—; such as from OH, halogen, ═O, COOH,        5-tetrazolyl, NO₂, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and        halo-(C₁-C₆)alkyl; e.g. from OH, ═O, COOH, 5-tetrazolyl,        (C₁-C₆)alkyl and (C₁-C₆)alkoxy;    -   (16) each R₆ is selected independently from ═O, (C₁-C₆)alkyl and        (C₁-C₆)alkoxy; e.g. ═O and (C₁-C₆)alkyl;    -   (17) each R₆ is selected independently from OH, halogen, COOH,        5tetrazolyl, NHOH, CONHOH, —CO—NH₂, NO₂, SH, NH₂, CN, CHO, ═O,        SO₂R₄ (wherein R₄ is as defined below), (C₁-C₆)alkyl,        (C₁-C₆)alkoxy and halo-(C₁-C₆)alkyl (e.g. CF₃); e.g. from COOH,        5-tetrazolyl, NHOH, CONHOH, —CO—NH₂ and SO₂R₄ (wherein R₄ is as        defined below) e.g. from COOH and 5-tetrazolyl;    -   (18) t is 1 and R₂ is OH, NO₂, SO₂R₄ (wherein R₄ is OH, NH₂ or        mono- or di(C₁-C₆)alkylamino, e.g. mono- or        di(C₁-C₆)alkylamino), (C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl,        (C₁-C₉)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N—        (unsubstituted or substituted with one to three, e.g. one or        two, e.g. one, substituents R₆), —(Y)_(n)—(B)_(m)—COOH (e.g.        —(B)_(m)—COOH or —Y—B—COOH) or —(Y)_(n)—(B)_(m)—R₅, wherein n is        0; or n is 1 and Y is CO; m is 0; or m is 1 and B is        (C₁-C₆)alkylene, e.g. —CH₂—; and R₅ is phenyl unsubstituted or        substituted with 1, 2 or 3, e.g. one or two, substituent(s) R₆        as defined above or below; e.g. with one or two, e.g. one, R₆        selected from with COOH or tetrazolyl; or R₅ is 5-tetrazolyl, or        R₅ is piperidinyl, piperazinyl, pyrrolyl, pyrrolinyl or        pyrrolidinyl, e.g. piperazin-1-yl, pyrrol-1-yl, pyrrolidin-1-yl        or pyrrolin-1-yl, unsubstituted or substituted with one or two        (C₁-C₆)alkyl or ═O, such as 4-(C₁-C₆)alkyl-piperazin-1-yl or        pyrrole-2,5-dion-1-yl;    -   (19) R₅ is e.g. phenyl substituted with one or two, e.g. one,        substituent(s) R₆ each selected independently from COOH,        5-tetrazolyl, —CO—NH₂, SO₂R₄ (wherein R₄ is as defined above or        below), NHOH and CONHOH, e.g. from COOH and 5-tetrazolyl; or R₅        is tetrazolyl, e.g. 5-tetrazolyl;    -   (20) R₅ is e.g. phenyl unsubstituted or substituted with one or        two R₆ as defined above or below or R₅ is tetrazolyl or R₅ is        piperazinyl, pyrrolyl or pyrrolinyl; each unsubstituted or        substituted with one or two OH, ═O, (C₁-C₆)alkyl, (C₁-C₆)alkoxy        (such as 4-(C₁-C₆)alkyl-piperazin-1-yl or        pyrrole-2,5-dion-1-yl);    -   (21) Y is CO;    -   (22) B is (C₁-C₆)alkylene; and/or    -   (23) R₄ is (C₁-C₆)alkyl, NH₂, OH or mono- or        di(C₁-C₆)alkylamino, e.g. NH₂, OH or mono- or        di(C₁-C₆)alkylamino, such as mono- or di(C₁-C₆)alkylamino.

A further subgroup of the compounds of formula I′ or I are the compoundsof formula Ia,

wherein the two OH— substituents are in a position ortho to one anotherand R1 in a position ortho to one of the hydroxy groups; and R₁ to R₃and t are as defined above.

A further subgroup of compounds Ia are compounds of formula Iaa

wherein R₁ to R₃ and t are as defined above.

Another subgroup of the compounds of formula I′ or I are the compoundsof formula Ib or Ic,

wherein R₁ to R₃ and t are as defined above.

In a further subgroup of compounds of formula I′, I, Ia, Iaa, Ib or Ic,R₁ is NO₂ CHO or CN, e.g. NO₂ or CN, such as NO₂; t is 1 or 2, and eachR₂ is selected independently from NO₂, SO₂R₄, (C₁-C₆)alkyl,NH₂—(C₁-C₆)alkyl, (C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N—(wherein phenyl is unsubstituted or substituted with one to three, e.g.one or two, e.g. one, substituents R₆), —(Y)_(n—(B)) _(m)—COOH (e.g.—(B)_(m)—COOH or —Y—B—COOH) and —(Y)_(n)—(B)_(m)—R₅, wherein n, m, B, Y,R₄, R₅ and R₆ are as defined above. In another subgroup of compounds I′,I, Ia, Iaa, Ib or Ic, t is 1 and R₂ is SO₂R₄, phenyl-N═N— (unsubstitutedor substituted with one to three, e.g. one or two, e.g. one,substituent(s) R₆), —(B)_(m)—COOH, —Y—B—COOH or —(Y)_(n)—(B)_(m)—R₅, nis 0; or n is 1 and Y is CO; m is 0; or m is 1 and (C₁-C₆)alkylene; R₅is phenyl, tetrazol-5-yl, piperidin-1-yl, piperazin-1-yl, pyrrol-1-yl,pyrrolidin-1-yl or pyrrolin-1-yl, wherein each of the said rings as R₅can be unsubstituted or substituted with one or two, substituent(s) R₆;each R₆ is selected independently from OH, halogen, NO₂, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, ═O, COOH and 5-tetrazolyl. For example phenyl as R₅ canbe unsubstituted or substituted with one or two, e.g. one, OH, halogen,NO₂, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, COOH or 5-tetrazolyl, e.g. COOH or5-tetrazolyl; A heterocyclyl as R₅ can be e.g. 5-tetrazolyl; orpiperidin-1-yl, piperazin-1-yl, pyrrol-1-yl, pyrrolidin-1-yl orpyrrolin-1-yl, e.g. piperazin-1-yl or pyrrol-1-yl, each optionallysubstituted with R₆ as defined above, e.g. with (C₁-C₆)alkyl,(C₁-C₆)alkoxy or ═O, (such as 4-(C₁-C₆)alkyl-piperazin-1-yl orpyrrole-2,5-dion-1-yl).

In another subgroup of the compounds I′, I, Ia, Iaa, Ib or Ic, t is 1 or2 and R₂ or, resp., at least one of R₂ is OH, halogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkoxy, NH₂—(C₁-C₆)alkyl, —CO—(C₁-C₉)alkyl,phenyl-N═N— (unsubstituted or substituted with one to three, e.g. one ortwo, e.g. one, substituent(s) R₆) or —(Y)_(n)—(B)_(m)—R₅, wherein n, m,B, Y, R₅ and R₆ are as defined above, e.g. R₂ is OH, (C₁-C₆)alkyl or or—(Y)_(n)—(B)_(m)—R₅, wherein n is 0, m is 0 and R₅ is phenylunsubstutited or optionally substituted with OH, halogen, (C₁-C₆)alkylor (C₁-C₆)alkoxy.

In a further subgroup of the compounds of formula Ia, Iaa, Ib or Ic, R₃is H, R₁ is at 5-position (according to the numbering depicted informula Iaa). In another subgroup of compounds Ia, Iaa, Ib or Ic, t is0, or t is 1 or 2, e.g. one. Yet in another subgroup of compounds Ia orIaa, R₂ (or one of R₂) is at 2-position.

The compounds of formula I′ and the subgroups I, Ia, Iaa, Ib and Ic, aswell as the pharmaceutically acceptable salts and the pharmaceuticallyacceptable esters thereof, are referred to below as the compounds of theinvention, unless otherwise indicated.

The compounds of the invention may have chiral carbon atom(s) in theirstructure. The invention includes within its scope all the possiblestereoisomers of the compounds I, including geometric isomers, e.g. Zand E isomers (cis and trans isomers), and optical isomers, e.g.diastereomers and enantiomers. Furthermore, the invention includes inits scope both the individual isomers and any mixtures thereof, e.g.racemic mixtures. The individual isomers may be obtained e.g. using thecorresponding isomeric forms of the starting material or they may beseparated after the preparation of the end compound according toconventional separation methods. For the separation of i.a. opticalisomers, e.g. enantiomers, from the mixture thereof the conventionalresolution methods, e.g. fractional crystallisation, may be used.

Physiologically acceptable salts may be prepared by known methods. Thepharmaceutically acceptable salts are the usual organic and inorganicsalts in the art. Furthermore, any COOH—, OH— and/oramino-functionality, such as COOH— and/or OH— functionality, e.g. COOH—functionality, when present in the compounds of the invention, can beconverted to a pharmaceutically acceptable ester or, respectively, apharmaceutically acceptable amide in a manner known in the art using apharmaceutically acceptable acid or, respectively, a pharmaceuticallyacceptable alcohol known from the literature. Examples of suchpharmaceutically acceptable acids and alcohols are e.g. aliphatic (e.g.C₁-C₉, such as C₁-C₆) acids and alcohols, or aromatic acids andalcohols, which are conventional in the field of pharmaceuticals andwhich retain the pharmacological properties of the free form.

Pharmaceutically acceptable salts include, when possible, also acidaddition salts conventionally used in the art.

Terms employed herein have the following meanings: A halogen or halorefers to fluorine, chlorine, bromine or iodine. The term (C₁-C₆)alkylas employed herein as such or as part of another group includes bothstraight and branched chain radicals of up to 6 carbon atoms, preferablyof 1, 2, 3 or 4 carbon atoms. In CO—(C₁-C₂₀)alkyl or CO—(C₁-C₉)alkyl thealkyl moiety includes both straight and branched chain radicals of up to20 or, resp., 9 carbon atoms, preferably of up to 6 carbon atoms, e.g.1, 2, 3 or 4 carbon atoms. The term (C₁-C₆)alkoxy as such or as part ofanother group refers to —O(C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is asdefined above. The term (C₂-C₆)alkenyl includes both straight andbranched chain radicals of up to 6 carbon atoms, preferably of 2, 3 or 4carbon atoms, containing double bond(s), e.g. one double bond. The termhalo-(C₁-C₆)alkyl as such or as part of another group refers to(C₁-C₆)alkyl radical, as defined above, that is substituted by one ormore halo radicals as defined above, e.g. trifluoromethyl,difluoromethyl etc. The term (C₁-C₆)alkylene refers to a straight orbranched, saturated hydrocarbon chain divalent radical, e.g. methylene,ethylene, propylene, butylene and the like. The term (C₂-C₆)alkenylenerefers to a straight or branched, unsaturated hydrocarbon chain divalentradical, wherein the unsaturation is present as one or more, e.g. one,double bond(s), e.g. vinylene, propenylene, butenylene etc. The term(C₃-C₇)cycloalkyl refers to a monocyclic 3- to 7-membered saturatedcarbocyclic ring, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl ring. The 5- to 10-membered heterocyclyl with one to fourheteroatoms selected independently from N, O and S means a mono- orbicyclic 5- to 10-membered, e.g. monocyclic 5- or 6-membered, partiallyor fully saturated, or aromatic hetero ring system. Examples of suchheterocyclyls include piperidinyl, piperazinyl, morpholinyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, isoindolinyl, tetrahydropyridyl,dihydropyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl etc., such astetrazolyl, e.g. 5-tetrazolyl, piperidinyl, piperazinyl, morpholinyl,pyrrolyl, pyrrolinyl and pyrrolidinyl.

In case of di(C₁-C₆)alkylamine, the (C₁-C₆)alkyl chains can be identicalor different.

It is evident to a skilled person that in the compounds I′, I, Ia, Iaa,Ib or Ic the nature of the optional substituent(s) R₆ and the maximalpossible number thereof in a ring R₅ depend on the nature of the ringR₅. E.g. the option ═O as R₆ is possible only for (C₃-C₇)cycloalkyl orsaturated or partially saturated heterocyclic rings as R₅, wherein adouble bond can be formed between the ring atom of R₅ and the saidoxygen atom.

The compounds of the invention can be prepared by a variety of syntheticroutes analogously or according to the methods known in the literatureusing suitable starting materials.

In general, the compounds of formula Iaa, wherein R₃ is H, R₁ is e.g.NO₂, t is 1 and R₂ is at 2-position can be prepared e.g. analogously oraccording to scheme 1:

wherein R₂ is as defined above, each R′ is a conventional protectinggroup for hydroxy, e.g. (C₁-C₆)alkyl, e.g. methyl.

According to the scheme 1 the hydroxy groups of a compound II areprotected in a conventional manner. Then a substituent R₂ is introducedto the protected compound III by an electrophilic aromatic substitutionreaction in a manner known in the art. By the term “electrophilicaromatic substitution reaction” the usual reactions known in the art aremeant, e.g. nitration, nitrosation, diazonium coupling, sulfonation,halosulfonation, halogenation, Friedel-Crafts alkylation and acylation,formylation by Vilsmeier, haloalkylation and acylation byHoesch-reaction just to mention the most known reactions. The compoundIV thus obtained is deprotected, and the deprotected product V isnitrated using e.g. diluted nitric acid in a suitable solvent, e.g. at(−20)° C.-0°C., to obtain an end compound Id.

The substituent R₂ can be converted, if desired, to anotherfunctionality of the invention in different stages of the preparation ofthe end compounds in a manner known to a skilled person, e.g. before orafter the introduction of R₁. The following schemes 2 and 3 illustratee.g. a further elaboration of the R₂ substituent before the introductionof R₁.

According to scheme 2, a protected compound VI (wherein R₂ is —CO—Ra, Rais alkyl, e.g. (C₁₋₅)alkyl, and, e.g. for the preparation of thespecific compounds VIII and IX, Ra is methyl) produced e.g. according tothe method of scheme 1 (cf. compound IV) can be subjected to aconventional reduction step to obtain a compound VII (wherein R₂ is—CH₂—Ra, Ra is alkyl, e.g. (C₁₋₅)alkyl, e.g. methyl), to a knownhypobromite reaction to obtain a compound VIII (wherein R₂ is —COOH) orto a known Dakin reaction to obtain compound IX (wherein R₂ is OH).

According to scheme 3, a compound X (wherein R₂ is NO₂) or XII (whereinR₂ is —CO—(CH₂)s—COOH, s is 1 to 5) produced e.g. according to themethod of scheme 1 (cf. compound IV) can both be subjected to areduction step to obtain a compound XI (wherein R₂ is NH₂) or,respectively, compound XII (wherein R₂ is —CH₂—(CH₂)s—COOH, s is 1 to5). The both reduction reactions are known in the chemical field.

Subsequently, the substituent R₁, e.g. a nitro group, is then introduced(e.g. after a deprotection step) to an intermediate compound VI, VII,VIII, IX, XI or XIII to obtain an end compound of the invention. Ifdesired, further optional substituents of the invention can also beintroduced to the above intermediate compounds before or after theintroduction of R₁.

The preparation of compounds Ib and Ic are illustrated in scheme 4 withspecific examples:

wherein R′ is a conventional protecting group for hydroxy, e.g.(C₁-C₆)alkyl, e.g. methyl, Alk is (C₁-C₆)alkyl, e.g. methyl, and hal ishalogen, e.g. Cl.

Compounds Ic of scheme 4A, wherein R₃ is H, t is 2 and one of R₂ is(C₁-C₆)alkyl, e.g. methyl, and the other is halogen, e.g. Cl, can beprepared according to the known Conrad-Limpach reaction procedure byreacting compound XIV with a compound XX in a suitable solvent and in anelevated temperature to obtain compound XV. Compound XV is then treatedwith PO(hal)3 to obtain compound XVI, which is deprotected and whereinthe substituent R₁, e.g. a nitro group, is introduced in a manner knownin the art to obtain an end compound Ic. Furthermore, compounds Ib ofscheme 4B, wherein R₃ is H and t is 0, can be prepared according to aprocedure known as Pomeranz-Fritsch synthesis, i.e. by reacting compoundXVII with a compound XXI in a suitable solvent and reaction conditionsto obtain compound XVIII which is then cyclized in acidic conditions toresult in compound XIX. Compound XIX can then be deprotected and asubstituent R₁, e.g. a nitro group, be introduced in a manner known inthe art to obtain an end compound Ic.

Examples of other synthetic routes which can be used for the preparationof compounds Ib and Ic of the invention i.a. Pictet-Spengler andBischler-Napieralski synthesis (for the preparation of compounds Ib) andDoebner-Miller and Doebner synthesis (for the preparation of compoundsIc) can be mentioned.

The starting material II, XIV, XVII, XX, XXI and other used reagents arecommercially available or can be prepared via a variety of knownsynthetic routes known in the literature or as described above or below.

It is obvious to a skilled person that, in the above reactions, anystarting material or intermediate can be protected, if necessary, in amanner well known in the chemical field. Any protected functionality issubsequently deprotected in a usual manner.

It should be noted that the above described synthetic routes are meantto illustrate the preparation of the compounds of the invention and thepreparation is by no means limited thereto, i.e. other synthetic methodswhich are within the general knowledge of a skilled person are alsopossible.

The compounds of the invention may be converted, if desired, into theirpharmaceutically acceptable salt or ester form using methods well knownin the art.

As already mentioned hereinbefore, the compounds of the invention showinteresting pharmacological properties, namely they exhibitcatechol-O-methyltransferase (COMT) enzyme inhibiting activity. The saidactivity of the compounds of the invention is demonstrated with thepharmacological tests presented below.

EXPERIMENT I: Determination of COMT activity (IC₅₀)

The determination of IC₅₀ was performed by measuring the COMT activityin a test sample which contained S-COMT enzyme (about 30 nM), 3 mMdopamine (as the substrate of COMT), 5 mM magnesium chloride, 0.05 mMS-adenosyl-L-methionine (AdoMet) and a test compound of the invention atvarious concentrations in 0.1 M phosphate buffer, pH 7.4, at 37° C.

The reaction in the test sample was initiated by adding the dopaminesubstrate to the sample mixture and, after incubation for 15 min at 37°C., the reaction was stopped with 4 M perchloric acid and stabilizedfurther 10 min in ice bath. Thereafter the precipitated proteins wereremoved by centrifugation (4000×G for 10 min). The activity of COMTenzyme was measured by determining the concentration of the reactionproducts, 3-methyldopamine and 4-methyldopamine, by HPLC. The resultswere calibrated with 3-methyldopamine standards. See also T. Lotta etal., Biochemistry, vol.34(13), 1995, p.4204. The IC₅₀ value is theconcentration of the test compound which causes a 50% decrease in COMTactivity. The results are shown in table 1.

TABLE 1 The compound of example no. IC50 (nM) Example 1 30 Example 3 80Example 4 25 Example 5 45 Example 7 30 Example 8 200 Example 9 80Example 10 15 Example 11 25 Example 13 100 Example 14 15 Example 15 140

Particularly, the compounds of the invention have preferable COMTinhibiting properties as therapeuticals. Accordingly, they can be usedfor the treatment of diseases or conditions wherein COMT inhibitors areindicated to be useful, i.a. in the treatment of Parkinson's diseasee.g. for the potentiation of levodopa (+DDC) therapy.

The compounds of the invention may be administered enterally, topicallyor parenterally.

The compounds of the invention may be formulated alone or together withone or more active agents and/or together with a pharmaceuticallyacceptable excipient in different pharmaceutical unit dosage forms, e.g.tablets, capsules, solutions, emulsions and powders etc., depending onthe route of adminstration, using conventional techniques. Thepharmaceutically acceptable excipient can be selected from thoseconventionally used in the field of pharmaceuticals noticing the chosenroute of administration.

The amount of the active ingredient varies from 0.01 to 100 weight-%depending on i.a. the type of the dosage form.

The specific dose level of the compounds of the invention depends, ofcourse, on several factors such as the compound to be administered, thespecies, age and the sex of the subject to be treated, the condition tobe treated and on the route and method of administration. For example,the compounds of the invention may administered from 0.5 μg/kg to 100mg/kg per day for an adult male.

The present invention also provides a compound of the invention or anester or salt thereof, or a pharmaceutical composition thereof, for usein a method of treatment of human or animal body.

The present invention further provides a compound of the invention or anester or salt thereof, as well as a pharmaceutical composition thereof,for use as a COMT inhibitor, i.a. for the treatment of diseases andconditions where inhibition of COMT enzyme is useful, e.g. for thetreatment of Parkinson's disease. The use of the compounds of theinvention for the manufacture of a medicament to be used for the aboveindications is also provided. The invention further relates to a methodfor the treatment of above indicated conditions or diseases, byadministering to a subject in need of such treatment an effective amountof the compound of the invention or a pharmaceutically acceptable esteror salt thereof.

The present invention will be explained in more detail by the followingexamples. The examples are meant only for illustrating purposes and donot limit the scope of the invention which is defined in claims. Theused starting material and reactants are commercially available.

EXAMPLE 1 1-Nitronaphthalene-2,3-diol, Method A

Fuming nitric acid (4.2 ml) was added to methylene chloride (50 ml) andthe resulting solution diluted with diethyl ether (100 ml): Then3-methylbuthylnitrite (1.9 ml) was added and this final solution addedat 25-30° C. to a solution of 2,3-dihydroxynaphthalene (16.0 g) in ether(100 ml).The reaction mixture was washed with water, extracted intopotassium bicarbonate (1 M), acidified and finally extracted into ether.After column chromatography (SiO2, toluene-ethyl acetate-acetic acid18:1:1) the product was crystallized from toluene. Yield: 1.5 g, meltingpoint 141-143° C.

¹H-NMR (DMSO-d₆, 400 MHz): 7.35 (s, 1H), 7.36-7.45 (m, 3H), 7.77 (dd,1H, J=7 Hz, n. 1 Hz), 10.8 (br s, 2H).

EXAMPLE 2 1-Nitronaphthalene-2,3-diol, Method B

(a) Naphthalene-2,3-diol Cyclohexylidene Ketal

The solution of naphthalene 2,3-diol (48.0 g), cyclohexanone and toluenesulfonic acid hydrate (1.0 g) in toluene (200 ml) was refluxed withwater separation (Dean-Stark) for 45 minutes. After washing with sodiumhydroxide (1 M, 300 ml) the organic phase was dried, evaporated andcrystallized from heptane. Yield: 40.8 g.

¹H-NMR (DMSO-d₆, 400 MHz): 1.46-1.53 (m, 2H),1.66-1.73 (m, 4H),1.92 (t,4H, j =6 Hz), 7.21 (s, 2H), 7.26-7.31 (m, 2H), 7.66-7.71 (m, 2H).

(b) 1-Nitronaphthalene-2,3-diol

To a solution of the product from the previous step (a) (14.4 g) inmethylene chloride (150 ml) a solution of fuming nitric acid (2.8 ml) inmethylene chloride (33 ml) was added at 15-20° C. After 30 minmethanesulfonic acid (70 ml) was added and the solution was boiled fortwo hours. The cooled reaction mixture was poured into ice water (600ml). The organic phase was separated and washed with water. The productwas extracted and purified as described in the previous example 1.Yield: 3.0 g. Physical characteristics as above.

EXAMPLE 3 (6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-phenyl-methanone

(a) (6,7-Dimethoxy-naphthalen-2-yl)-phenyl-methanone

Aluminum chloride (16.0 g) was added to a solution of2,3-dimethoxynaphthalene (18.0 g) and benzoylchloride (12.0 g) in coldmethylene chloride (400 ml) and the solution was stirred overnight.After treatment with cold water the phases were separated and themethylene chloride phase washed with 1 M sodium hydroxide. The productwas triturated with warm ether. Yield: 7 g, melting point 124-125° C.

¹H-NMR (DMSO-d₆, 400 MHz): 8.17(s, 1H), 7.9 (d, 1H, J=9 Hz), 7.18 (d,2H, J=Hz), ,72 (dd, 2H, 7, 1.5 Hz), 7,68 (d, 1H, J=9 Hz), 7.59 (dd,2H,J=7, 6.5 Hz), 7.53 (s,1H), 7.43 (s,1H), 3.94 (s,3H), 3.89 (s,3H).

(b) (6,7-Dihydroxy-naphthalen-2-yl)-phenyl-methanone

The product from the previous step (a) (5 g) was heated in pyridiniumhydrochloride (30 g) at 220° C. for 15 minutes, cooled to 150-160° C.,poured into ice water filtered and washed with water. Yield: 4.2 g,melting point 176-193° C.

¹H-NMR (DMSO-d₆, 400 MHz): 10 (b,1H, OH), 9.8 (b,1H, OH),8.01 (s,1H),7.67-7.77 (m,3H), 7.57-7.59 (m,2H), 7.27 (s, 1H) 7.23 (s,1H).

(c) (6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-phenyl-methanone

The product from the previous step (b) (2.64 g) was slurried in ether(100 ml), N,N-dimethylacetamide (3 ml) added and the resulting solutioncooled to 0° C. Nitric acid in methylene chloride (2 M, 5 ml) wasgradually added and then stirred 30 minutes at ambient temperature. Thereaction mixture was evaporated, triturated with water and decanted. Theresulting oil was dried in the oven and then purified by columnchromatography (SiO₂, toluene-THF-acetic acid 8:1:1.The product wasfinally triturated with methyl-t-buthyl ether. Yield: 0.18 g, meltingpoint 196-205° C.

¹H-NMR (DMSO-d₆): 11.3 (b,2H, OH), 7.96 (d,1H, J=8 Hz), 7.82 (s,1H),7.68-7.78 (m,5H), 7.57-7.61 (m,2H) 7.46 (s,1H).

EXAMPLE 41-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-2-methyl-propan-1-one

(a) 1-(6,7-Dimethoxy-naphthalen-2-yl)-2-methyl-propan-1-one

The solution of 2,3-dimethoxynaphthalene (16.5 g ), isobutyroylchloride(12.5 g) and aluminum chloride (15.7 g) in methylene chloride (200 ml)was stirred at ambient temperature overnight. The solution was thenwashed with saturated sodium bicarbonate and water, dried with sodiumsulfate and evaporated. Finally the crude product was triturated withether. Yield: 13.5 g, melting point 103-105° C.

¹H-NMR (DMSO-d₆): 8.51 (s,1H), 7.83 (s,2H), 7.53 (s,1H), 7.39 (s,1H),(s,3H). 3.91 (s,3H), 3.76-3.80 (m,1H), 1.16 (d,6H, J=8 Hz).

(b) 1-(6,7-Dihydroxy-naphthalen-2-yl)-2-methyl-propan-1-one

The product from the previous step (a) (13.5 g) and pyridiniumhydrochloride (100 g) were heated at 220-225° C. for 30 minutes. Thereaction mixture was treated with water and extracted with ether. Thecrude product was triturated with petroleum ether (40-60° C.).Yield:11.2 g, melting point 154-156° C.

¹H-NMR (DMSO-d₆): 9.9 (b,2H,OH), 8.35 (s,1H), 7.65-7.71 (m,2H), 7.32(s,1H), 7.17 (s,1H), 3.74-3.79 (m,1H), 1.14 (d,6H, J=7 Hz).

(c) 1-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-2-methyl-propan-1-one

Nitric acid in methylene chloride (2 M, 1.4 ml) was gradually added tothe solution of the product from the previous step (b) (0.65 g) in ethylacetate (10 ml) at −10° C. After 20 min at 0° C. the solvents wereevaporated. FLASH-chromatography on silica with toluene-ethylacetate-acetic acid 8:1:1 as the solute and then trituration withether-petroleum ether (40-60° C.) yielded the raw product which wasfinally recrystallized from ethyl acetate-heptane. Yield: 0.13 g,melting point 197-204° C.

¹H-NMR (DMSO): 11.3 (b,2H,OH), 8.05 (s,1H), 7.90 (m,2H), 7.42 (s,1H),3.68-372 (m,1H), 1.14 (d,6H, J=7 Hz).

EXAMPLE 5 6-Isobutyl-1-nitro-naphthalene-2,3-diol

Sodium borohydride (0.55 g) was added to a solution of the product fromexample 4(c) (0.33 g) in trifluoroacetic acid (11 ml). The reactionmixture was stirred at ambient temperature for two hours, poured intowater, extracted with ethyl acetate, dried, evaporated andrecrystallized from ethanol-water. Yield: 0.22 g, melting point 105-108°C.

¹H-NMR (DMSO-d₆): 10.68 (b,2H,OH), 7.69 (d,1H, J=8 Hz), 7.31 (s,1H),7.20 (d,1H, J=8 Hz), 7.15 (s,1H), 2.52-2.55 (m,2H), 1.84-1.87 (m,1H),0.85-0.87 (m,6H).

EXAMPLE 6 1-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-pentadecan-1-one

(a) 1-(6,7-Dimethoxy-naphthalen-2-yl)-pentadecan-1-one

The solution of 2,3-dimethoxynaphthalene (1.9 g), palmitoyl chloride(3.2 ml) and aluminium chloride (1.5 g) in methylene chloride (40 ml)was stirred at ambient temperature overnight. The reaction mixture wasworked up as described in example 4(a). The crude product wasrecrystallized from ethyl acetate-heptane. Yield 2.0 g.

¹H-NMR (CDCl₃): 8.33 (d,1H, J=1.5 Hz), 7.90 (dd,1H, J=8.8 and 1.5 Hz),7.72 (d,₁H, J=8.8 Hz), 7.23 (s,1H), 7.14 (s,1H), 4.02 (s,3H), 4.03(s,3H), 3.05 (2H, J=7.4 Hz), 1.78 (m,2H), 1.25-1.45 (m, 24H), 0.88(t,3H, J=7 Hz).

(b) 1-(6,7-Dihydroxy-naphthalen-2-yl)-pentadecan-1-one

The product from the previous step (a) (3.6 g) and pyridiniumhydrochloride (36 g) were heated for one hour at 220° C. Work-up asdescribed in example 3(b). Yield: 2.7 g, melting point 133-134° C.

¹H-NMR (DMSO-d₆): 9.97 (s,1H,OH), 9.78 (s,1H,OH), 8.32 (s,1H), 7.62-7.70(m,2H), 7.30 (s,1H), 7.16 (s,1H), 3.03-3.07 (m,2H), 1.61-1.65(m,2H),1.23-1.3 (m,24H), 0.83-0.86 (m,3H).

(c) 1-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-pentadecan-1-one OR-1770

Nitric acid in methylene chloride (2 M, 3.5 ml) was gradually added to asolution of the product from the previous step (b) (2.8 g) in ethylacetate (500 ml) at 0° C. The reaction mixture was stirred at roomtemperature overnight and then at 50° C. for two hours. Afterevaporation the product was purified by column chromatography asdescribed in example 4(c). The crude product was recrystallized fromethyl acetate and triturated with ether. Yield: 0.1 g, melting point128-130° C.

¹H-NMR (DMSO-d₆): 11.2 (b,2H), 8.04 (s,1H), 7.88 (s, 2H), 7.41 (s,1H),3.02-3.06 (m,2H), 1.58-1.63 (m,2H), 1.15-1.36 (m,24H), 0.82-0.86(m,3H).

EXAMPLE 7 6,7-Dihydroxy-5-nitro-naphthalene-2-carboxylic Acid

(a) 6,7-Dimethoxy-naphthalene-2-carboxylic Acid

Bromine (4.6 ml) was added to sodium hydroxide solution (2.5 M, 130 ml)at 0° C. After 5 minutes on ice the solution was warmed to 35° C. Then asolution of the product from example 3(a) (4.6 g) in dioxane (30 ml) wasadded. The reaction mixture was stirred 20 min at 35° C., cooled to21-23° C. and then a bisulphite solution (4 g Na₂S₂O₅ in 40 ml water)added. After 30 minutes at 23° C. water (200 ml) was added and thereaction mixture was once washed with methylene chloride (100 ml). Thewater phase was separated and kept on ice for an hour, filtered andwashed with water. Yield: 4.2 g, melting point 256-258° C.

¹H-NMR (DMSO-d₆): 12.82 (s,1H,COOH), 8.45 (s,1H), 7.78-7.83 (m,2H), 7.49(s,1H), 7.36 (s,1H), 3.91 (s,3H), 3.90 (s,3H).

(b) 6,7-Dihydroxy-naphthalene-2-carboxylic Acid

The product from the previous step (a) (2 g) and pyridine hydrochloride(12 g) were heated at 220° C. for 15 minutes. The reaction mixture wasworked up with acidic water (pH 2-3), filtered and washed with water.Yield: 1.6 g, melting point 241-250° C.

¹H-NMR (DMSO-d₆): 12.67 (b,1H,COOH), 9.95 (s,1H,OH), 9.75(s,1H,OH),8.26. (s,1H), 7.62-7.69 (m,2H), 7.26 (s,1H), 7.17 (s,1H).

(c) 6,7-Dihydroxy-5-nitro-naphthalene-2-carboxylic Acid

Nitric acid in methylene chloride (2 M, 2.5 ml) was gradually added to asolution of the product from the previous step (b) (1 g) in acetone (10ml) at 0° C. and stirred for an hour at that temperature. The reactionmixture was worked up as described in example 6(c). The purified productwas finally recrystallized from ether. Yield: 0.1 g, melting point over310° C.

¹H-NMR (DMSO-d₆): 12.7-13.3 (b,1H,COOH), 11-11.5 (b,2H;OH), 8.07(s,1H),7.83-7.89 (m,1H), 7.42 (s,1H).

EXAMPLE 8 2,3-Dihydroxy-naphthalene-1-carbaldehyde

Phosphorous oxychloride (1.9 ml) was added to a solution of2,3-dihydroxynaphthalene (3.2 g) in DMF (26 ml) at 0° C. The reactionmixture was kept for four hours at 100° C. Water (50 ml) was added tothe cooled mixture and the resulting oily suspension refluxed for 20min. The cool reaction mixture was poured into ice, filtered, washedwith water and recrystallized from 2-propanol-water. Yield: 0.1 g,melting point 129-134° C.

¹H-NMR (DMSO-d₆): 10.5-12 (b,2H,OH), 10.82 (s,1H,CHO), 8.76 (d,1H, J=8Hz), 7.71 (dd,1H, J=8 and 1 Hz), 7.47 (s,1H), 7.35-7.44(m,2H).

EXAMPLE 9 1-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-heptan-1-one

(a) 1-(6,7-Dimethoxy-naphthalen-2-yl)-heptan-1-one

Aluminium chloride (2.66 g) was added to a solution of:heptanoylchloride (3.1 ml) and 2,3-dimethoxynaphthalene (3.76 g) inmethylene chloride (50 ml) at 0° C. The reaction mixture was stirred atroom temperature overnight and then worked up as described in example3(a). The crude product was recrystallized from ethanol. Yield: 2.8 g,melting point 77-78° C.

¹H-NMR (DMSO-d₆, 400 MHz): 8.49 (s,1H), 7.81 (s,2H), 7.51 (1H); 7.18(s,1H) 3.92 (s,3H), 3.91 (s,3H), 3.07 (t,2H, J=8 Hz), 1.61-1.68 (m,2H),1.29-1.37 (m,8H), 0.87 (t,3H, J=8 Hz).

(b) 1-(6,7-Dihydroxy-naphthalen-2-yl)-heptan-1-one

The product from the previous step (a) (2.6 g) and pyridiniumhydrochloride (34 g) were heated at 225° C. for 20 minutes. The reactionmixture was allowed to cool to 150-160° C. and then poured into ice. Thecrude product was taken in 2-propanol and precipitated with water.Yield: 2.0 g.

¹H-NMR (DMSO-d₆, 400 MHz): 9.99 (s,1H,OH), 9.80 (s,1H,OH), 8.34 (s,1H),7.64-7.71 (m,2H), 7.32 (s,1H), 7.18 (s,1H), 3.07 (t,2H, J=8 Hz),1.61-1.68 (m,2H), 1.31-1.35 (m,8H), 0.88 (m,3H).

(c) 1-(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-heptan-1-one

Nitric acid in methylene chloride (2 M, 2.5 ml) was gradually added to asolution of the product from the previous step (b) (1.36 g) in ethylacetate (80 ml) at 0° C. The reaction mixture was worked up as describedin example 4(c). The crude product was recrystallized from toluene.Yield: 50mg, melting point 97-98° C.

¹H-NMR (DMSO-d₆, 400 MHz): 11.22 (b,2H,OH), 8.04 (s,1H), 7.88 (s,1H),7.41 (s,1H), 3.04 (t,2H, J=8 Hz), 1.60-1.63 (m,2H), 1.27-1.32 (m,8H),0.86 (m,3H)

EXAMPLE 10 1,6-Dinitro-naphthalene-2,3-diol

(a) Acetic Acid 3-hydroxy-naphthalen-2-yl Ester

Acetylchloride (0.71 ml) was added to a solution of2,3-dihydroxynaphthalene (1.6 g) and pyridine (0.81 ml) in ethyl acetate(20 ml) at 0° C. The mixture was stirred for few hours at roomtemperature and then washed with water, dried and evaporated to dryness.The crude product was recrystallized from ether. Yield: 0.52 g.

¹H-NMR (DMSO-d₆, 400 MHz): 10.09 (s,1H,OH), 7.71-7.77 (m,2H), 7.57(s,1H), 7.38-7.41 (m,1H), 7.28-7.32 (m,1H), 7.27 (s,1H), 2.31 (s,3H).

(b) Acetic Acid 3-hydroxy-4,7-dinitro-naphthalen-2-yl Ester

Nitric acid in methylene chloride (2 M, 2.9 ml) was gradually added to asolution of the product from the previous step (a) (0.5 g) in ethylacetate (20 ml) at 0° C. The mixture was stirred an additional half anhour at room temperature, cooled to 0° C. and filtered. Yield: 0.39 g.

¹H-NMR (DMSO-d₆, 400 MHz): 9.01 (s,1H), 8.32 (d,1H, J=8 Hz), 8.28(s,1H), 7.79 (d,1H, J=8 Hz), 2.40 (s,3H).

(c) 1,6-Dinitro-naphthalene-2,3-diol

Two drops of concentrated hydrochloric acid was added to a solution ofthe product from the previous step (b) (0.37 g) in methanol (20 ml) andthis solution stirred for 16 hours at 50° C. Methanol was evaporated andthe rest triturated with ether. Yield: 0.11 g, melting point 200-207° C.

¹H-NMR (DMSO-d₆, 400 MHz): 10.8-12 (b,2H,OH), 8.89 (s,1H), 8.12 (d,1H,J=4 Hz), 7.68 (s,1H), 7.65 (d,1H, J=4 Hz).

EXAMPLE 11 6,7-Dihydroxy-5-nitro-naphthalene-2-sulfonic AcidDipropylamide

(a) 6,7-Dihydroxy-naphthalene-2-sulfonic Acid Dipropylamide

The suspension of 2,3-dihydroxynaphthalene-6-sulphonic acid sodium salt(2.6 g), acetic acid (20 ml), acetic anhydride (10 ml) and sulphuricacid (0.6 ml) was refluxed for 30 minutes. Volatiles were removed underreduced pressure and the remaining solids were refluxed in thionylchloride (20 ml) for 30 minutes. Volatiles were again evaporated andthen methylene chloride (30 ml) and dipropylamine (6.8 ml) added andthis mixture stirred at room temperature for two hours. The reactionmixture was washed with 1 M hydrochloric acid (70 ml) and the organicphase evaporated. To the remaining solids were added methanol (100 ml)and concentrated hydrochloric acid (20 ml) and this mixture was stirredat room temperature for 22 hours. Diethyl ether (400 ml) was added andthe organic phase was washed three times with water. Ether wasevaporated. Yield: 1.3 g.

¹H-NMR (DMSO-d₆, 400 MHz): 0.81 (t, 6H, J=7 Hz), 1.40-1.52 (m, 4H), 3.03(t, 4H, J=8 Hz), 7.21 (s, 1H), 7.33 (s, 1H), 7.45 (dd, 1H, J=9 Hz, 2Hz), 7.75 (d,1H, J=9 Hz), 8.09 (d, 1H, J=2 Hz),), 9.9 (s, 1H), 10.1 (s,1H).

(b) 6,7-Dihydroxy-5-nitro-naphthalene-2-sulfonic Acid Dipropylamide

Nitric acid in methylene chloride (0.17 ml in 2.0 ml) was added to asolution of the product from the previous step (a) (1.26 g) in ethylacetate (20 ml) at 0-5° C. The reaction mixture was washed with waterand evaporated. Column chromatography on silica with toluene-ethylacetate-acetic acid 23:1:1 as the eluent yielded a crude product (150mg) from which part was further purified by HPLC (C-18/acetonitrile, 20mM pH=3, phosphate buffer 41.5:58.5).

¹H-NMR (DMSO-d₆, 400 MHz): 0.81 (t, 6H, J=7 Hz), 1.42-1.53 m, 4H), 3.05(t, 4H, J=8 Hz), 7.60 (s, 1H), 7.62, (d, 1H, J=8 Hz), 7.70 (dd, 1H, j=8Hz, 2 Hz), 8.34 (d, 1H, J=2 Hz), n. 11.0 (brs, 2H).

EXAMPLE 12 6,7-Dihydroxy-8-nitro-naphthalene-2-sulfonic AcidDipropylamide

The other isomer separated by HPLC from example 11(b).

¹H-NMR (DMSO-d₆, 400 MHz): 0.80 (t, 6H, J=7 Hz), 1.40-1.51 (m, 4H), 3.05(t, 4H, J=8 Hz), 7.46 (s, 1H), 7.68 (dd, 1H, j=9 Hz, 2 Hz), 7.84 (dd,1H, J=2 Hz, <1 Hz) 8.00 (d,1H, J=9 Hz), n. 11.0 (br s, 2H).

EXAMPLE 13 2,3-Dihydroxy-naphthalene-1-carbonitrile

(a) 2,3-Dimethoxy-naphthalene-1-carbaldehyde

n-Butyl lithium in hexane (1.6 N, 31.3 ml) was gradually added to asolution of 2,3-dimethoxynaphthalene (9.4 g) andN,N,N′,N′-tetramethylethylenediamine (7.4 ml) in ether (150 ml) underargon at 0° C. The reaction mixture was stirred at room temperature fortwo hours, cooled to 0° C. and DMF (7.3 g) in ether (20 ml) added. Thereaction mixture was stirred at room temperature overnight and poured inice water. The product was extracted with ether, washed with water,dried, evaporated and recrystallized from ether. Yield: 4.2 g.

¹H-NMR (DMSO-d₆, 400 MHz): 10.68 (s,1H, CHO), 8.95-8.97 (m, 1H),7.87-7.89 (m,1H), 7.80 (s,1H), 7.49-7.51 (m,2H), 4.00 (s,6H).

(b) 2,3-Dimethoxy-naphthalene-1-carbaldehyde Oxime

The mixture of the product from the previous step (a) (2.0 g),hydroxylamine hydrochloride (0.55 g), water (5 ml), ethanol (6 ml) andsodium hydroxide solution (2.5 N, 3 ml) was refluxed for an hour.Ethanol was evaporated, the solids filtered, washed with water and thecrude product recrystallized from ethanol. Yield: 1.25 g,

¹H-NMR (DMSO-d₆, 400 MHz): 11.50 (s,1H), 8.73 (d, 1H, J=8 Hz), 8.62(s,1H), 7.73 (d,1H, J=8 Hz), 7.49 (s,1H), 7.39-7.46 (m,2H), 3.95 (s,3H),3.83 (s,3H).

(c) 2,3-Dimethoxy-naphthalene-1-carbonitrile

The solution of the product from the previous step (b) (1.2 g) andacetic anhydride (15 ml) was refluxed for 20 minutes. The volatiles wereevaporated and the product recrystallized from ethanol. Yield: 0.96 g.

¹H-NMR (DMSO-d₆, 400 MHz): 7.94-7.96 (m,1H), 7.88-7.89 (m, 1H), 7.82(s,1H) 7.55-7.62 (m,3H), 4.06 (s,3H), 3.96 (s,3H).

(d) 2,3-Dihydroxy-naphthalene-1-carbonitrile

Boron tribromide (0.8 ml) was added to the solution of the product fromthe previous step (c) (0.45 g) in methylene chloride (25 ml) undernitrogen at −20° C. The mixture was stirred at room temperature for twodays, poured into ice water, filtered and the product recrystallizedfrom ethanol. Yield: 0.25 g, sublimates.

¹H-NMR (DMSO-d₆, 400 MHz): 10.89 (bs, 2H, OH), 7.74-7.76(m, 2H),7.35-7.47 (m,3H).

EXAMPLE 14(6,7-Dihydroxy-5-nitro-naphthalen-2-yl)-(4-methyl-piperazin-1-yl)-methanone

Thionyl chloride (0.3 ml) and DMF (one drop) were added to thesuspension of the product from example 7(c) (0.35 g) in toluene (10 ml),the mixture was stirred at 80-85° C. for two hours and the volatilesevaporated. The remaining solid was taken in methylene chloride (10 ml),cooled to 0-5° C. and N-methylpiperazine (0,16 ml) in methylene chloride(2 ml) was added gradually. The reaction mixture was stirred for 20minutes at 0-5° C. and then the product precipitated by adding ether.The resulting solid was suspended in water and neutralized with 1 MNaOH, filtered and washed with water. The crude product was twicerecrystallized from ethanol. Yield: 50 mg, melting point over 360° C.

¹H-NMR (DMSO-d₆, 400 MHz): 7.76 (s,1H), 7.66 (d,1H, J=(8.6 Hz), 7.16(s,1H), 2.77 (b, 4 H), 2.5 (b, 7 H).

EXAMPLE 15 5-Bromo-6,7-dihydroxy-8-nitro-isoquinolinium; Bromide

(a) 6,7-Dimethoxy-8-nitro-isoquinoline

To a solution of 6,7-Dimethoxy-isoquinolinone (2.88 g) in sulphuric acid(20 ml) at 5-10° C. was added 2 M HNO₃—H₂SO₄-solution (8 ml) and thereaction mixture stirred overnight at ambient temperature. The reactionmixture was poured into ice water, pH adjusted to 12 and the productextracted in methylene chloride. The methylene chloride phase wasextracted with 1 M HCl , the pH of the aqueous phase adjusted to 12 andextracted into methylene chloride, dried and evaporated. Yield: 2.5 g.

(b) 5-Bromo-6,7-dihydroxy-8-nitro-isoquinolinium; Bromide

The product from the previous step (a) (2.5 g) and 47% hydrobromic acid(50 ml) were refluxed for 12 hours, the reaction mixture evaporated andthe product recrystallized from ethanol. Yield: 0.47 g.

¹H-NMR (DMSO-d₆, 400 MHz): 7.65 (d, 1 H, J=5.6 Hz), 8.05 (d, 1 H, J=5.6Hz), 9.18 (s, 1H). Mass spectrum: M=284 (100%), 286 (98%), 1 Br.

EXAMPLE 16 1-Nitro-6-phenylazo-naphthalene-2,3-diol

To the suspension of the product from example 1 (0.41 g) in water (10ml), sodium hydroxide solution (5 M, 0.4 ml) and sodium acetate (0.66 g)were added. The reaction mixture was cooled to 0° C. andbenzenediazonium chloride-solution (from 0.18 ml of aniline and 0.14 gNaNO₂) was gradually added. After 10 minutes at 0° C. the solution wasacidified with 6 M hydrochloric acid, filtered and washed with water.The crude product was triturated with ethanol. Yield: 0.25 g, meltingpoint 238-244° C.

¹H-NMR (DMSO-d₆): 16.11 (b,1H,OH), 11.5 (b,1H,OH), 8.43 (d,1H, J=8 Hz),7.85 (d,2H, J=8 Hz), 7.38-7.58 (m,5H), 7.23 (d,1H, J=8 Hz).

EXAMPLE 17 1-(6,7-Dihydroxy-naphthalen-2-ylmethyl)-pyrrole-2,5-dione

(a) 6-Chloromethyl-2,3-dimethoxy-naphthalene

A solution of the product from preparation example 4(b) (3.14 g) andthionyl chloride (1.6 ml) in methylene chloride (30 ml) was refluxed forthree hours. The reaction mixture was evaporated, toluene added andevaporated again. The product was used as such in the following step.

(b) 2-(6,7-Dimethoxy-naphthalen-2-ylmethyl)-isoindole-1,3-dione

To a solution of the product from the previous step (a) in DMF (15 ml)was added potassium phthalimide (2.6 g). After stirring overnight atambient temperature the reaction mixture was poured in water, extractedinto methylene chloride, washed with 1 N sodium hydroxide, dried andevaporated. The resulting mixture was used as such in the followingstep. (Yield of mixture: 3.3 g).

(c) C-(6,7-Dimethoxy-naphthalen-2-yl)-methylamine

The product mixture from the previous step (b) (3.3 g) and hydrazinhydrate (0.71 ml) in ethanol (100 ml) was refluxed for 8 hours. Thereaction mixture was filtered, the filtrate evaporated, triturated withmethylene chloride and filtered again. The second filtrate was extractedwith 1 M hydrochloric acid, the pH of the aqueous phase taken to 11-12,extracted into methylene chloride again, dried and evaporated. Yield:0.21 g.

(d) 6-Aminomethyl-naphthalene-2,3-diol; Hydrobromide

The product from the previous step (c) (0.21 g) and 47% hydrobromic acid(10 ml) were refluxed for 5 hours. The reaction mixture was evaporated.Yield: 0.23 g.

(e) 3-[(6,7-Dihydroxy-naphthalen-2-ylmethyl)-carbamoyl]-acrylic acid

To a solution of the product of the previous step (d) (0.23 g) andtriethyl amine (0.12 ml) in DMF (3 ml) on ice bath was added maleicanhydride (80 mg). The resulting mixture was stirred at ambienttemperature overnight and then poured into ice water. The pH wasadjusted to 3 and the product filtered. Yield: 125 mg.

(f) 1-(6,7-Dihydroxy-naphthalen-2-ylmethyl)-pyrrole-2,5-dione

The product from the previous step (e) (125 mg) was refluxed in aceticacid (2 ml) for 20 hours and evaporated. The product was purified bycolumn chromatography on silica with eluent toluene-ethyl acetate-aceticacid 8:9:1. The product was finally triturated with ether. Yield: 18 mg,melting point 182-187° C.

¹H-NMR (DMSO-d₆, 400 MHz): 4.64 (s, 2H, CH2), 7.03-7.06 (m, 3H), 7.07(s, 2H, CH═CH), 7.39 (br, 1H), 7.51 (d, J=8,4 Hz), 9.6 (br, 2H, OH).

EXAMPLE 181-(6,7-Dihydroxy-5-nitro-naphthalen-2-ylmethyl)-pyrrole-2,5-dione

1-Nitronaphthalene-2,3-diol (0.77 g) produced according to example 1above and 1-hydroxymethyl-pyrrole-2,5-dione produced according topreparation example 6 below, (0.47 g) were mixed thoroughly and thenadded in portions to sulphuric acid at 0-5° C. After 30 minutes on icebath the reaction mixture was poured into ice water and filtered. Afterchromatography on silica, eluent toluene-ethyl acetate-acetic acid8:1:1, the product was recrystallized from acetone. Yield: 12 mg,melting point over 350° C.

¹H-NMR (DMSO-d₆, 400 MHz): 4.69 (s, 2H, CH₂), 7.08 (s, 2H, CH═CH), 7.22(dd, 1H, J=8.4, 1.6 Hz), 7.28 (d, 1H, J=1.6 Hz), 7.32 (s, 1H), 7.73 (d,1H, J=8.4 Hz), 10.8 (br, 2H, OH).

PREPARATION EXAMPLE 1 6-Benzyl-naphthalene-2,3-diol

Sodium borohydride (0.44 g) was carefully added to a solution of theproduct from example 3(b) above (0.5 g) in trifluoroacetic acid (20 ml)under nitrogen. The mixture was then stirred at ambient temperatureovernight. After treatment with ice water the product was extracted inether which was dried and evaporated. The crude product wasrecrystallized from ethanol-water (2:3). Yield: 0.34 g, melting point177-187° C.

¹H-NMR (DMSO-d₆): 9.44 (s,1H,OH), 9.40 (s,1H,OH), 7.48 (d,1H, J=8.4 Hz),7.41 (s,1H), 7.23-7.28 (m,4H), 7.17-7.18 (m,1H), 7.03-7.06 (m,3H), 3.98(s,2H)

PREPARATION EXAMPLE 2 3-Methoxy-1,6-dinitro-naphthalen-2-ol

(a) 3-Methoxy-naphthalen-2-ol

Dimethylsulfate (32 ml) was added to the solution of2,3-dihydroxynaphthalene (32 g) and sodium hydroxide (10 M, 32 ml) inwater (300 ml). After being stirred for six hours at room temperature,the side product 2,3-dimethoxynaphthalene was filtered off (yield 16.6g). The water phase was acidified, stirred on ice bath, filtered, washedwith water and recrystallized from ethanol-water (3:2). Yield: 13.5 g,melting point 108-109° C.

¹H-NMR (DMSO-d₆): 9.47 (b,1H), 7.69-7.71 (m,1H), 7.60-7.62 (m,1H),7.22-7.27 (m,3H), 7.14 (s,1H),3.90 (s,3H).

(b) 3-Methoxy-1,6-dinitro-naphthalen-2-ol

Nitric acid in methylene chloride (2 M, 10.0 ml) was added to a solutionof the product from the previous step (a) (1.74 g) in methylene chloride(20 ml) at 0° C. The mixture was stirred on ice for an hour and then theprecipitated product was filtered. Yield: 1.63 g, melting point 239-242°C.

¹H-NMR (DMSO-d₆): 11.7-12.4 (b,1H,OH), 9.00 (d,1H, J=2 Hz), 8.28 (dd,1H,J=9 and 2 Hz), 8.07 (s,1H), 7.77 (d,1H, J=9 Hz), 4.13 s,3H).

PREPARATION EXAMPLE 3 4-(6,7-Dihydroxy-naphthalen-2-yl)4-oxo-butyricAcid

(a) 4-(6,7-Dimethoxy-naphthalen-2-yl)-4-oxo-butyric Acid

Aluminium chloride (9.5 g) was added to a solution of2,3-dimethoxynaphthalene (10 g) and succinic anhydride 7.1 g inmethylene chloride (140 ml). The mixture was stirred at room temperatureovernight and then treated with water and filtered. The resulting solidwas taken into 1 M sodium hydroxide, washed once with methylenechloride, acidified and filtered. Yield: 8.3 g, melting point 215-229°C.

¹H-NMR (DMSO-d₆): 12.15 (s,1H,CO₂H), 8.53 (s,1H), 7.83 (s,1H), 7.54(s,1H), 7.39 (s,1H), 3.92 (s,3H), 3.91 (s,3H), 3.33-3.36 (m,2H),2.60-2.63 (m,2H).

(b) 4-(6,7-Dihydroxy-naphthalen-2-yl)-4-oxo-butyric Acid

The product from the previous step (a) (2 g) and pyridiniumhydrochloride (12 g) were heated to 225° C. for 15 minutes. The reactionmixture was allowed to cool to 150-160° C. and then poured into ice. Theproduct was extracted into ethyl acetate and recrystallized from2-propanol-water. Yield: 0.44 g.

¹H-NMR (DMSO-d₆, 400 MHz): 12.12 (b,1H,COOH), 9.90 (b,2H,OH), 8.36(s,1H), 7.70 (dd,1H, J=8 and 1 Hz), 7.65 (d,1H, J=8 Hz), 7.32 (s,1H),7.18 (s,1H), 331-3.34 (m,2H), 2.59-2.62 (m,2H).

PREPARATION EXAMPLE 4 (6,7-Dimethoxy-naphthalen-2-yl)-methanol

(a) 6,7-Dimethoxy-naphthalene-2-carbonyl Chloride

DMF (two drops) and thionylchloride (1.9 ml) were added to a suspensionof the product from example 7(a) above (3 g) in toluene (50 ml). Thereaction mixture was stirred at 80° C. under nitrogen for 200 minutes.The solution was evaporated, toluene added and evaporated again. Theproduct was used as such in the next step.

¹H-NMR (CDCl₃): 8.59 (d,1H, J=1.7 Hz), 7.96 (dd,1H, J=8.4, 1.7 Hz), 7.76(d,1H, J=8.4 Hz), 7.27 (s,1H), 7.18 (s,1H), 4.07 (s,3H), 4.05 (s,3H).

(b) (6,7-Dimethoxy-naphthalen-2-yl)-methanol

Lithiumaluminum hydride (1.3 g) was added to a solution of the productfrom the previous step (a) in THF (50 ml) and the suspension refluxedunder nitrogen for 30 minutes. Ethyl acetate (10 ml) was added to thecooled reaction mixture and then the whole suspension was poured intoice water, acidified and extracted into ethyl acetate. The ethyl acetatephase was then washed with water, dried and evaporated. Yield: 3.7 g.

¹H-NMR (DMSO-d₆, 400 MHz): 7.66-7.73 (m,2H), 7.29-7.32(m,1H), 7.27(s,2H),5.2 (t,1H, J=5.7 Hz,OH), 4.61 (d,2H, J=5.7 Hz), 3.88 (s,6H).

PREPARATION EXAMPLE 54-(6,7-Dihydroxy-naphthalene-2-carbonyl)-1-methyl-piperazin-1-ium;Chloride

(a) 6,7-Dihydroxy-naphthalene-2-carbonyl Chloride

DMF (two drops) and thionyl chloride (1.6 ml) were added to thesuspension of the product from example 7(b) above (1.5 g) in toluene (20ml). The mixture was stirred at 80° C. for 4 hours, decanted andevaporated. Yield: 1.6 g.

¹H-NMR (CDCl₃, 400 MHz): 8.79 (s,1H) 8.15 (d,1H, J=8 Hz), 8.00 (d,1H,J=8 Hz), 7.82 (s,1H), 7.72 (s,1H).

(b) 4-(6,7-Dihydroxy-naphthalene-2-carbonyl)-1-methyl-piperazin-1-ium;Chloride

N-Methylpiperazine (0.7 g) in methylene chloride (5 ml) was added to asolution of the product from the previous step (a) (1.5 g) in methylenechloride (15 ml) at 0° C. The reaction mixture was stirred 45 minutes onice bath, diluted with ether and filtered. Yield: 1.7 g, melting point176-180° C.

¹H-NMR (DMSO-d₆, 400 MHz): 11.02 (b,1H), 9.84 (s,1H), 9.77 (s,1H), 7.70(s 1H),7.64 (d,1H, J=4 Hz), 7.17-7.24 (m, 3H), 3.34-3.41 (m,8H), 2.76(s, 3H)

PREPARATION EXAMPLE 6 1-Hydroxymethyl-pyrrole-2,5-dione

Maleimide (2.0 g) and 10% formaline (6.8 g) were stirred at 100° C. for60 minutes. The reaction was let to cool and then kept overnight at 4°C. The product was filtered, washed with water and ethanol. Yield: 1.3g, melting point 96,5-97° C.

¹H-NMR (DMSO-d₆, 400 MHz): 7.07 (s,2H), 6.27 (t,1H, J=7 Hz), 4.78 (d,2H,J=7 Hz).

PREPARATION EXAMPLE 7 1-Bromo-naphthalene-2,3-diol

(a) 1-Bromo-3-methoxy-naphthalen-2-ol

A solution of bromine (0.26 ml) in methylene chloride (5 ml) wasgradually added to the solution of the product from preparation example2(a) (0.87 g) in methylene chloride (10 ml) at 0° C. The reactionmixture was evaporated and recrystallized from 60% ethanol. Yield: 1.1g, melting point 100-101° C.

¹H-NMR (DMSO-d₆): 9.9 (b,1H,OH), 7.93 (d,1H,J=7.9 and 0.9 Hz), 7.32-7.46(m,1H), 7.40 (s,1H), 7.34-7.38 (m,1H).

(b) 1-Bromo-naphthalene-2,3-diol

Boron tribromide solution in methylene chloride (1 M, 6 ml) wasgradually added to a solution of the product from the previous step (a)(0.5 g) in methylene chloride (10 ml) at −10° C. After being stirred twohours below 0° C., the reaction was quenched with ice water and thephases separated. The water phase was extracted with methylene chloride,the combined organic phases washed with water, dried and evaporated.Recrystallization from ethyl acetate-heptane. Yield: 0.32 g, meltingpoint 98-102° C.

¹H-NMR (DMSO-d₆): 10.51 (s,1H,OH), 9.71 (s,1H,OH), 7.88 (d,1H, J=9 Hz),7.66 (d,1H, J=8 Hz), 7.27-7.38 (m,2H), 7.18 (s,1H).

PREPARATION EXAMPLE 84-Chloro-1-(6,7-dihydroxy-naphthalen-2-yl)-butan-1-one

(a) 4-Chloro-1-(6,7-dimethoxy-naphthalen-2-yl)-butan-1-one

This product was prepared from 2,3-dimethoxynaphthalene (3.76 g),aluminium chloride (2.93 g) and 4-chlorobutanoylchloride (2.96 g) inmethylene chloride (100 ml) as described in example 9(a) above.

¹H-NMR (DMSO-d₆, 400 MHz): 8.51 (s,1H), 7.83 (s,2H), 7.54 (s,1H), 7.39(s,1H), 3.93 (s,3H), 3.91 (s,3H), 3.76 (t,2H, J=6.6 Hz), 3.28 (t, 2H,J=7.0 Hz), 2.09-2.16 (m,2H).

(b) 4-Chloro-1-(6,7-dihydroxy-naphthalen-2-yl)-butan-1-one

The product from the previous step (a) (2 g) was reacted with borontribromide as described in preparation example 7(b). The crude productwas triturated with ether. Yield: 0.11 g, melting point 129-135° C.

¹H-NMR (DMSO-d₆, 400 MHz): 9.90 (b,2H), 8.34 (s,1H), 7.64-7.71 (m,2H),7.31 (s,1H), 7.12 (s,1H), 3.74 (t,2H, J=8 Hz), 3.24 (t,2H), 2.07-2.14(m,2H).

PREPARATION EXAMPLE 92-Chloro-1-(6,7-dihydroxy-naphthalen-2-yl)-ethanone

(a) 2-Chloro-1-(6,7-dimethoxy-naphthalen-2-yl)-ethanone

2,3-Dimethoxynaphthtalene (2.80 g), aluminium chloride (3.33 g) and3-chloropropionyl chloride (2.79 g) were reacted in methylene chloride(40 ml) as described in example 6(a) above. Yield: 2.87 g, melting point137-140° C.

¹H-NMR (DMSO-d₆): 8.54 (s,1H), 7.84 (s,1H), 7.54 (s,1H), 7.40 (s,1H),3.97-4.00 (m,2H), 3.93 (s,3H), 3.92 (s,3H), 3.63-3.66 (m,2H).

(b) 2-Chloro-1-(6,7-dihydroxy-naphthalen-2-yl)-ethanone

The product from the previous step (a) (1 g) was demethylated with borontribromide as described in preparation example 7(b) above. Yield: 0.43g, melting point over 320° C.

¹H-NMR (DMSO-d₆): 9.5-10.5 (b,2H,OH), 8.38 (s,1H), 7.65-7.72 (m,2H),7.33 (s,1H), 7.18 (s,1H), 3.95-3.98 (m,2H), 3.60-3.63 (m,2H).

PREPARATION EXAMPLE 10 6,7-Dimethoxy-naphthalene-2-carbaldehyde

2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) (1.14 g) was gradually addedto the solution of the product from preparation example 4(b) above (1.09g) in dioxane (25 ml) and the reaction mixture stirred at roomtemperature overnight. The precipitated DDQ-H₂ was filtered and thefiltrate evaporated. The resulting solids were triturated with methylenechloride and filtered. The filtrate was evaporated and recrystallizedfrom ethanol. Yield: 0.61 g, melting point 87-88° C.

¹H-NMR (DMSO-d₆, 400 MHz): 10.07 (s,1H,CHO), 8.37 (s,1H), 7.89 (d,1H,J=8 Hz), 7.74 (d,1H, J=8 Hz), 7.54 (s,1H), 7.44 (s,1H), 3.94 (s,3H),3.93 (s,3H).

PREPARATION EXAMPLE 11 Acetic Acid 6,7-dimethoxy-naphthalen-2-ylmethylEster

Acetyl chloride (0.32 ml) was added to the solution of the product frompreparation example 4(b) above (1.0 g) and triethyl amine (0.63 ml) inmethylene chloride (20 ml) at 0° C. The reaction mixture was allowed toreach room temperature and then it was washed with water, the organicphase dried and evaporated. Yield: 1.2 g, melting point 71-75° C.

¹H-NMR (DMSO-d₆, 400 MHz): 7.72-7.75 (m,2H), 7.29-7.31 (m,3H), 5.18(s,2H), 3.88 (s,6H), 2.09 (s,3H).

1. A compound of formula I,:

wherein the two OH— substituents in the phenyl moiety are in a positionortho to one another and R₁ is in a position ortho to one of the hydroxygroups; and wherein “A” is a fused ring moiety selected from a benzoring and a 6-membered heteroaromatic ring which contains one or two Nheteroatoms; t is 1,2,3 or 4; R₁ is NO₂, CN, CHO or CF₃; and each R₂ isselected independently from OH, halogen, NO₂, SH, NH₂, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkoxy, OH—(C₁-C₆)alkyl, NH₂—(C₁-C₆)alkyl,halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino, SO₂R₄,(C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl, -CO—, phenyl-N═N— optionallysubstituted with one to three substituents R₆,—(Y)_(n)—(Y)_(n)—(B)_(m)—R₅; R₃ is H, NO_(2,) CN, CHO, halogen, CF₃ orCH₃; and R₄ is (C₁-C₆)alkyl, NH₂, OH or mono- or di(C₁-C₆)alkylamino; mis 0 or 1; n is 1; Y is —CO— or —CHOH—; B is (C₁-C₆)alkylene or(C₂-C₆)alkenylene; R₅ is phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- to10-membered heterocyclyl with one to four heteroatoms each selectedindependently from N, O and S, wherein the said phenyl, naphthyl,(C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclyl is optionallysubstituted with one to five substituents R₆ or R₅ is

each R₆ is selected independently from OH, halogen, COOH, 5-tetrazolyl,NO₂, SH, NH₂, CN, CHO, ═O, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino, CO—(C₁-C₆)alkyl,CO—NH₂, mono- or di(C₁-C₆)alkylamino-CO—, NHOH, CONHOH and SO₂R₄; or apharmaceutically acceptable salt or pharmaceutically acceptable ester orpharmaceutically acceptable amide thereof.
 2. A compound of claim 1,which is a compound of formula Ia:

wherein the two OH— substituents are in a position ortho to one anotherand R₁ is in a position ortho to one of the hydroxy groups; and R₁ to R₃and t are as defined in claim 1, or a pharmaceutically acceptable saltor pharmaceutically acceptable ester or pharmaceutically acceptableamide thereof.
 3. A compound of claim 1, which is a compound of formulaIaa:

wherein R₁ to R₃ and t are as defined in claim 1, or a pharmaceuticallyacceptable salt or pharmaceutically acceptable ester or pharmaceuticallyacceptable amide thereof.
 4. A compound of claim 1, which is a compoundof formula Ib or Ic:

wherein R₁ to R₃ and t are as defined in claim 1, or a pharmaceuticallyacceptable salt or pharmaceutically acceptable ester or pharmaceuticallyacceptable amide thereof.
 5. A compound according to claim 1, wherein R₁is NO₂, CHO or CN.
 6. A compound according to claim 5, wherein R₁ isNO₂.
 7. A compound according to claim 1, wherein R₃ is H.
 8. A compoundaccording to claim 1, wherein t is 1 or 2 and each R₂ is selectedindependently from OH, NH₂, halogen, NO₂, SO₂R₄, (C₁-C₆)alkyl,NH₂—(C₁-C₆)alkyl, (C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N—,wherein phenyl is optionally substituted with one to threesubstituent(s) R₆, —(Y)_(n)—(B)_(m)—COOH and —(Y)_(n)—(B)_(m)—R₅.
 9. Acompound according to claim 1, wherein R₂ is phenyl-N═N, wherein phenylis optionally substituted with one or two substituent(s) R₆,—(Y)_(n)—(B)_(m)—COOH or —(Y)_(n)—(B)_(m)—R₅, wherein n is 1 and Y isCO; m is 0 or 1 and B is (C₁-C₆)alkylene.
 10. A compound according toclaim 1, wherein R₅ is phenyl optionally substituted with one or twosubstituent(s) R₆ selected independently from OH, halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, COOH and tetrazolyl; or R₅ is tetrazol-5-yl,piperidin-1-yl, piperazin-1-yl, pyrrol-1-yl, pyrrolin-1-yl orpyrrolidin-1-yl, each optionally substituted with one or twosubstituent(s) R₆ selected independently from (C₁-C₆)alkyl,(C₁-C₆)alkoxy and ═O.
 11. A compound according to claim 10, wherein R₅is phenyl optionally substituted with one or two R₆, or R₅ istetrazol-5-yl, 4-(C₁-C₆)alkyl-piperazin-1-yl or pyrrole-2,5-dion-1-yl.12. A compound according to claim 10, wherein R₅ is tetrazol-5-yl orphenyl which is optionally substituted with one or two COOH ortetrazolyl.
 13. A pharmaceutical composition which comprises as anactive agent a compound of formula I′:

wherein the two OH— substituents in the phenyl moiety are in a positionortho to one another and R₁ is in a position ortho to one of the hydroxygroups; and wherein “A” is a fused ring moiety selected from a benzoring and a 6-membered heteroaromatic ring which contains one or two Nheteroatoms; R₁ is NO₂, CN, CHO, CF₃ or (C₁-C₆)alkyl-CO—; t is 0, 1,2,3or 4; each R₂ is selected independently from OH, halogen, NO₂, SH, NH₂,(C₁-C₆)alkyl, (C₂C₅)alkenyl, (C₁-C₆)alkoxy, OH—(C₁-C₆)alkyl,NH₂—(C₁-C₆)alkyl, halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino,SO₂R₄, (C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N— optionaliysubstituted with one to three substituents R₆, —(Y)_(n)—(B)_(m)—COOH and—(Y)_(n)—(B)_(m)—R₅; R₃ is H, NO₂, CN, CHO, halogen, CF₃ or(C₁-C₆)alkyl; and R₄ is (C₁-C₆)alkyl, NH₂, OH or mono- ordi(C₁-C₆)alkylamino; m is 0 or 1; n is 1; Y is —CO— or —CHOH—; B is(C₁-C₆)alkylene or (C₂-C₆)alkenylene; R₅ is phenyl, naphthyl,(C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclyl with one to fourheteroatoms each selected independently from N, O and S, wherein thesaid phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- to 10-memberedheterocyclyl is optionally substituted with one to five substituents R₆;or R₅ is

each R₆ is selected independently from OH, halogen, COOH, 5-tetrazolyl,NO₂, SH, NH₂, CN, CHO, ═O, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino, CO—(C₁-C₆)alkyl,CO—NH₂, mono- or di(C₁-C₆)alkylamino-CO—, NHOH, CONHOH and SO₂R₄; or apharmaceutically acceptable salt or pharmaceutically acceptable ester orpharmaceutically acceptable amide thereof, and a pharmaceuticallyacceptable excipient.
 14. A method for treating Parkinson's Disease,which comprises administering to a mammal in need of the treatment aneffective amount of levodopa and an effective amount of the compound offormula I′:

wherein the two OH— substituents in the phenyl moiety are in a positionortho to one another and R₁ is in a position ortho to one of the hydroxygroups; and wherein “A” is a fused ring moiety selected from a benzoring and a 6-membered heteroaromatic ring which contains one or two Nheteroatoms; R₁ is NO₂, CN, CHO, CF₃ or (C₁-C₆)alkyl-CO—; t is 0, 1,2,3or 4; each R₂ is selected independently from OH, halogen, NO₂, SH, NH₂,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy, OH—(C₁-C₆)alkyl,NH₂—(C₁-C₆)alkyl, halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino,SO₂R₄,(C₁-C₂₀)alkyl-CO—, halo-(C₁-C₆)alkyl-CO—, phenyl-N═N- optionallysubstituted with one to three substituents R₆,—(Y)_(n)—(B)_(m)—COOH and—(Y)_(n)—(B)_(m)—R₅; R₃ is H, NO₂, ON, CHO, halogen, CF₃ or(C₁-C₆)alkyl; and R₄ is (C₁-C₆)alkyl, NH₂, OH or mono- ordi(C₁-C₆)alkylamino; m is 0 or 1; n is 1; Y is —CO— or —CHOH—; B is(C₁-C₆)alkylene or (C₂-C₆)alkenylene; R₅ is phenyl, naphthyl,(C₃-C₇)cycloalkyl or 5- to 10-membered heterocyclyl with one to fourheteroatoms each selected independently from N, O and S, wherein thesaid phenyl, naphthyl, (C₃-C₇)cycloalkyl or 5- to 10-memberedheterocyclyl is optionally substituted with one to five substituents R₆or R₅ is

each R₆ is selected independently from OH, halogen, COOH, 5-tetrazolyl,NO₂,SH, NH₂, CN, CHO, ═O , (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo-(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino, CO—(C₁-C₆)alkyl,CO—NH₂, mono- or di(C₁-C₆)alkylamino-CO—, NHOH, CONHOH and SO₂R₄; orpharmaceutically acceptable salt or pharmaceutically acceptable ester orpharmaceutically acceptable amide thereof to potentiate the levodopatherapy.
 15. A method for treating Parkinson's Disease, which comprisesadministering to a mammal in need of the treatment an effective amountof levodopa and an effective amount of a compound according to claim 1to potentiate levodopa therapy.
 16. A pharmaceutical composition whichcomprises as an active agent a compound according to claim 1 and apharmaceutically acceptable excipient.